The present invention relates to liquid polymeric compositions; for instance, such compositions for controlled release of at least one bioactive substance, e.g., at least one hydrophobic bioactive substance, such as a liquid polymeric composition which can form a film encapsulated liquid, e.g., in situ and/or which can achieve a long-term sustained release in a patient or host (e.g., animal or human) such as plasma profiles showing high efficacy (greater than about 70%, such as at least about 80%, preferably at least about 90%, e.g., about 100% efficacy for greater than about 12 months and/or plasma levels sustained for at least about 50 or about 60 days or at least about two months or at least about eight weeks, e.g., at least about 90 days or about three months or about 12 weeks or at least about 120 days or about four months or about 16 weeks, or at least about 150 days or about five months or about 20 weeks, or even longer, e.g., up to about a year or more; for instance, from 1 to 12 months.
The present invention further relates to a liquid polymeric composition comprising: (1) about 1-30% w/v bioactive substance (e.g., hydrophobic bioactive substance); (2) about 1-20% w/v of a biologically acceptable xe2x80x9cpolymerxe2x80x9d (including xe2x80x9ccopolymerxe2x80x9d, a polymer polymerized by at least two comonomers) (e.g., poly(lactide-co-glycolide) copolymer), for instance, wherein the weight ratio of the polymer to the bioactive substance can be 1:1 or less, e.g., 0.3:1 to 1:1; and (3) at least one lipophilic solvent or a mixture of hydrophilic and lipophilic solvents wherein the volume ratio of the hydrophilic and lipophilic solvents is from about about 80:20 to about 0:100, for instance about 80:20 to about 10:90 or 5:95, hydrophilic and lipophilic solvents, e.g., about 65:35 to about 35:65, and/or wherein the the water immiscible or lipophilic solvent is present in an amount of at least about 16.5% by weight (e.g., including about 16.465% by weight), such as at least about 16.5% to about 45% by weight, for instance at least about 16.5% to about 30% by weight (e.g., at least about 29% by weight) or at least greater than 40% by weight (for instance and at least about 42-45% by weight); e.g., such compositions wherein there is less than 10% of the polymer and 1 to 10% of the bioactive active substance or about less than 7% (e.g., 6.7%) or 5% or less polymer, with the bioactive substance content at less than or equal to about 10% or 5%.
The present invention yet further relates to a liquid polymeric composition consisting essentially of the foregoing, wherein the liquid polymeric composition is capable of forming a film encapsulated liquid, e.g., in situ, and/or having long-term sustained release, wherein the term xe2x80x9cconsisting essentially ofxe2x80x9d is used in the sense attributed to it in patent documents, and the term is exclusionary as to ingredients which may impede the capability of the composition to so form a film encapsulated liquid.
The present invention still further relates to methods for making and using such compositions. For example, a method of making such compositions comprising admixing the aforementioned ingredients; for instance, preferably dissolving both the polymer and the bioactive substance (as opposed to suspending, encapsulating, or having present as a solid, the bioactive substance, which, while not necessarily excluded by the invention, may be less preferable to dissolving). Or, a method for using such compositions comprising administering to a patient or host (animal, e.g., mammal such as domesticated animal, for instance companion animal or feedstock animal, or human) an inventive composition.
These and other areas to which the invention relates will be apparent from the following text. Various documents are cited in the following text, without any admission that any of these documents are prior art as to the invention. All documents cited in this text, as well as all documents referenced in documents cited in this text, are hereby incorporated herein by reference.
Biodegradable polymers have been used in parenteral controlled release formulations of bioactive compounds. In one approach the polymer is fabricated into microspheres that may be injected via syringe, and the bioative compound is entrapped within the microspheres. This approach has not proved to be practical in part due to the difficulty in the manufacturing procedure for producing sterile and reproducible products, and the high cost of manufacturing. In another approach the biodegradable polymer and the bioactive material are dissolved in a biocompatible water-miscible solvent to provide a liquid composition. When the liquid composition is injected into the body, the solvent dissipates into the surrounding aqueous environment, and the polymer forms a solid depot from which the bioactive material is released.
European Patent Application 0537559 concerns polymeric compositions having a thermoplastic polymer, rate modifying agent, water soluble bioactive material and water-miscible organic solvent. Upon exposure to an aqueous environment (e.g. body fluids) the liquid composition is capable of forming a biodegradable microporous, solid polymer matrix for controlled release of water soluble or dispersible bioactive materials over about four weeks. The thermoplastic polymer may be, among many listed, polylactide, polyglycolide, polycaprolactone or copolymers thereof, and is used in high concentration (45 to 50%). The rate modifying agent may be, among many others listed, glycerol triacetate (triacetin); however, only ethyl heptanoate is exemplified; and the amount of the rate modifying agent is no more than 15%.
Indeed, with respect to the patent literature, reference is made to:
These documents tend to provide compositions that form a solid, gel or coagulated mass; for instance, a significant amount of polymer is contemplated in these documents, akin to European Patent Application 0537559.
Mention is also made of: Shah et al (J. Controlled Release, 1993, 27:139-147), as relating to formulations for sustained release of bioactive compounds containing various concentrations of poly(lactic-co-glycolic) acid copolymer (PLGA) dissolved in vehicles such as triacetin; Lambert and Peck (J. Controlled Release, 1995, 33:189-195), as a study of the release of protein from a 20% PLGA solution in N-methylpyrrolidone exposed to aqueous fluid; and Shivley et al (J. Controlled Release, 1995, 33:237-243), as a study of the solubility parameter of poly(lactide-co-glycolide) copolymer in a variety of solvents, and the in vivo release of naltrexone from two injectable implants (5% naltrexone in either 57% PLGA and 38% N-methylpyrrolidone or 35% PLGA and 60% N-methylpyrrolidone).
There is nonetheless a need for long term sustained-release compositions, as well as polymeric compositions which can form film coated or encapsulated liquids.
In contrast to previous compositions, it has surprisingly been found that a polymeric composition containing a substantially greater amount of water immiscible or lipophilic solvent and substantially less polymer than contemplated by the literature results in a formulation which tends to stay as a film-coated (encapsulated) liquid rather than form a solid, gel or coagulated mass (including xe2x80x9cpore-containingxe2x80x9d solids, gels or masses as in the literature). It does not appear that the use or amount of the lipophilic solvent and the low amount of polymer used in the liquid polymeric formulations of the invention is contemplated by the prior art.
Accordingly, an object of the invention can be any or all of: to provide a liquid polymeric composition including a bioactive substance, for instance, such a composition that has long-term sustained release and/or forms a film-coated or encapsulated liquid, as well as to provide methods for making and/or using such a composition.
The present invention provides liquid polymeric compositions; for instance, such compositions for controlled release of at least one bioactive substance, e.g., at least one hydrophobic bioactive substance, such as a liquid polymeric composition which can form a film encapsulated liquid, e.g., in situ and/or which can achieve a long-term sustained release in a patient or host (e.g., animal or human) such as plasma profiles showing high efficacy (greater than about 70%, such as at least about 80%, preferably at least about 90%, e.g., about 100% efficacy for greater than about 12 months and/or plasma levels sustained for at least about 50 or about 60 days or at least about two months or at least about eight weeks, e.g., at least about 90 days or about three months or about 12 weeks or at least about 120 days or about four months or about 16 weeks, or at least about 150 days or about five months or about 20 weeks, or even longer, e.g., up to about a year or more; or from 1 to 12 months or longer.
The present invention further provides a liquid polymeric composition comprising: (1) 1-30% w/v of at least one bioactive substance (e.g., hydrophobic bioactive substance); (2) 1-20% w/v of at least one biologically acceptable xe2x80x9cpolymerxe2x80x9d (including xe2x80x9ccopolymerxe2x80x9d, a polymer polymerized by at least two comonomers) (e.g., poly(lactide-co-glycolide) copolymer), for instance, wherein the weight ratio of the polymer to the bioactive substance can be 1:1 or less, e.g., 0.5:1 to 1:1; and (3) a mixture of at least one hydrophilic solvent and at least one lipophilic solvent, e.g., at least one biologically or physiologically or medically or veterinarily acceptable hydrophilic solvent and at least one biologically or physiologically or medically or veterinarily acceptable lipophilic solvent wherein the volume ratio of the hydrophilic and lipophilic (or hydrophobic) solvents is from about 80:20 to about 0:100, for instance about 80:20 to about 10:90 or 5:95, hydrophilic and lipophilic solvents, e.g., about 65:35 to about 35:65, and/or wherein the water immiscible or lipophilic solvent is present in an amount of at least about 16.5% by weight (e.g., including 16.465% by weight), such as at least about 16.5% to about 45% by weight, for instance at least about 16.5% to about 30% by weight (eg., at least about 29% by weight), or at least about 20% or about 25% by weight to about 30%, 35%, 40% or 45% by weight, or at least greater than 40% by weight (for instance and at least about 42-45% by weight); e.g., such compositions wherein there is less than 10% of the polymer and 1 to 10% of the bioactive active substance or about less than 7% (e.g., 6.7%) or 5% or less polymer, with the bioactive substance content at less than or equal to about 10% or 5%.
The present invention yet further provides a liquid polymeric composition consisting essentially of the foregoing, wherein the liquid polymeric composition is capable of forming a film encapsulated liquid, e.g., in situ, and/or having long-term sustained release, wherein the term xe2x80x9cconsisting essentially ofxe2x80x9d is used in the sense attributed to it in patent documents, and the term is exclusionary as to ingredients which may impede the capability of the composition to so form a film encapsulated liquid. Thus, for instance, an agent which would tend to cause the composition, e.g., in situ, to have one or more contrary properties, e.g., an agent which would tend to cause the composition to solidify, such as a curing agent, or to form pores, may not be desired in certain embodiments.
The present invention still further provides methods for making and using such compositions. For example, a method of making such compositions comprising admixing the aforementioned ingredients; for instance, preferably dissolving both the polymer and the bioactive substance (as opposed to suspending, encapsulating, or having present as a solid, the bioactive substance, which, while not necessarily excluded by the invention, may be less preferable to dissolving). Or, a method for using such compositions comprising administering to a patient or host (animal, e.g., mammal such as domesticated animal, for instance companion animal or feedstock animal, or human) an inventive composition.
The invention additionally provides methods consisting essentially of at least one step for making or using such compositions; wherein the liquid polymeric composition is capable of forming a film encapsulated liquid, e.g., in situ, and/or having long-term sustained release, wherein the term xe2x80x9cconsisting essentially ofxe2x80x9d is used in the sense attributed to it in patent documents, and the term is exclusionary as to ingredients which may impede the capability of the composition to so form a film encapsulated liquid. Thus, for instance, a step which would tend to cause the composition, e.g., in situ, to have one or more contrary properties, e.g., adding an agent which would tend to cause the composition to solidify, such as a curing agent, or to form pores, may not be desired in certain embodiments.
The bioactive substance may be any biologically agent which is capable of providing a biological, physiological or therapeutic effect in an animal or human. The biologically active agent may be any one or more of known biologically active agents recognized in any document cited herein or otherwise recognized in the art. The agent may also stimulate or inhibit a desired biological or physiological activity within the animal or human, including without limitation, stimulate an immunogenic or immunological response.
Accordingly, the invention provides an in situ formed film coated or encapsulated liquid implant capable of functioning as a delivery system of drugs, medicaments, and other biologically-active agents to tissues adjacent to or distant from the implant site. The biologically-active agent is preferably incorporated into the film coated or encapsulated liquid, and subsequently released into surrounding tissue fluids and to the pertinent body tissue or organ. The composition may be administered to the implant site by any suitable method for applying a liquid, as for example, by means of a syringe, needle, cannula, catheter, pressure applicator, and the like. Exemplary biologically active agents or bioactive substances include, without limitation, fipronil, avermectin, ivermectin, eprinomectin, milbemycin, phenylpyrazole, nodulisporic acid, estradiol benzoate, tremblone acetate, noresthisterone, progesterone an antibiotic such as a macrolide or azalide antibiotic, or a non-steroidal anti-inflamatory drugs (NSAID), or combinations thereof. Thus, an object of the invention can be to provide delivery of at least one active ingredient, regardless of whether the ingredient is water insoluble or immiscible; but, the invention is especially applicable to hydrophobic biologically active substances.
The biologically acceptable polymer can be any biologically acceptable polymer, such as a biologically acceptable polymer recognized in documents cited herein. For instance, the biologically acceptable polymer can have one or more or all of the following characteristics: be bioerodible by cellular action, biodegradable by action of non-living body fluid components, soften when exposed to heat but return to the original state when cooled and are capable of substantially dissolving or dispersing in a water-miscible carrier or solvent to form a solution or dispersion. Upon contact with an aqueous fluid and the polymer are capable of assisting in the formation of the film coated or encapsulated liquid. The kinds of polymers suitable for the present composition generally include any having the foregoing characteristics. Examples are polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malicacid), poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures therein. Polylactides, polycaprolactones, polyglycolides and copolymers thereof are preferred polymers, with poly(lactide-co-glycolide) copolymer (xe2x80x9cPLGAxe2x80x9d) highly preferred. The constitution of PLGA can be akin to its use in the Examples below or in documents cited herein.
The solvents can be any biologically or physiologically or medically or veterinarily hydrophobic and water miscible solvents such as those recognized in documents cited herein.
The hydrophilic solvent may be chosen from propylene glycol, PEG, polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400, di(ethylene glycol)ethyl ether (Transcutol), isopropylidene glycerol(Solketal), dimethyl isosorbide (Arlasolve DMI), propylene carbonate, glycerol, glycofural, pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone, isopropylidene glycerol, di(propyleneglycol) methyl ether, and mixtures thereof. Other solvents may also be useful as the hydrophilic solvent. For instance, the hydrophilic solvent can be a C2 to C6 alkanol (e.g., ethanol, propanol, butanol), acetone, alkyl esters such as methyl acetate, ethyl acetate, ethyl lactate, alkyl ketones such as methyl ethyl ketone, dialkylamides such as dimethylformamide, dimethyl sulfoxide, dimethyl sulfone, tetrahydrofuran, cyclic alkyl amides such as caprolactam, decylmethylsulfoxide, oleic acid, propylene carbonate, aromatic amides such as N,N-diethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one. The hydrophilic solvent can be a mixture of solvents.
The lipophilic or non-water-miscible or hydrophobic solvent may be chosen from triethyl citrate, Miglyol 812, Miglyol 840, Crodamol GTCC, triacetin or benzyl benzoate; and additional lipophilic solvents may be used, e.g., hydrophobic rate modifying agents or plasticizers such as fatty acids, triglycerides, triesters of glycerol, oils such as castor oil, soybean oil or other vegetable oils or derivatives thereof such as epoxidized or hydrogenated vegetable oils such as epoxidized soybean oil or hydrogenated castor oil, sterols, higher alkanols (e.g., C6 or higher), glycerin and the like. The lipophilic solvent can be a mixture of solvents.
Other solvents can include: glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, di(ethylene glycol)ethyl ether acetate, di(propylene glycol)methyl ether (Dowanol DPM), di(propylene glycol)methyl ether acetate, glycerol formal, glycofurol, isopropyl myristate, N,N,-dimethyl acetamide, PEG 300, propylene glycol, and polar, aprotic solvents such as DMSO.
In certain embodiments there can be less than 10% of the polymer and 1 to 10% of the active compound; for instance, the proportion of the PLGA polymer and the active compound is less than or equal to 1:1. (See, e.g., the Example, wherein for instance 0.25 75/25 PLGA was dissolved in glycerol formal to provide a 2.5 ml solution; in a separate flask 75/25 PLGA was dissolved in triacetin to provide a 2.5 ml solution; the two solutions were mixed and added to a flask containing 0.50 g active ingredient which was dissolved into the mixed PLGA solutions; the amount of triacetin present in the formulation to be about 42% by weight; other formulations contain as little as 6.7% and 5% PLGA content with the drug content at 10% or 5%.)
When implanted, i.e., upon injection, the inventive liquid formulation forms what appears to be, from gross examination of the host or patient into which the formulation is implanted, xe2x80x9ca semi-solid depot with a skin made of polymer.xe2x80x9d The depot, though, without necessarily wishing to be bound by any one particular theory, is not necessarily solid or semi-solid (as that term may be usually understood); but rather, is a film coated or encapsulated liquid (the polymer assisting in the skin formation). Over time, depot loses its vehicle(s) (solvent(s) and degradation of the polymer occurs.
While there is diffusion through the film (typically whitish in color in preferred embodiments), it is believed that there are no pores in the depot; and it likely that the liquid polymeric formulation does not form in situ, a solid, or a coagulated mass or a gelatinous mass. These beliefs are based on the fact that the amount of polymer in the inventive formulation is substantially less than that used in the prior art; the amount of water immiscible or lipophilic solvent present in inventive formulations is substantially greater than any xe2x80x9crate modifying agentxe2x80x9d or similar solvent used in the prior art (allowing the core of the depot to remains liquid); and, as the active ingredient diffuses through the film (a very, very thin film, usually whitish in preferred embodiments), the polymer biodegrades. The inventive formulation, is well-suited for delivering lipophilic (hydrophoblic) active ingredients.
These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.